The present invention relates to a chemical process for the manufacture of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propanenitrile, the compound of formula I, and its use as an intermediate in the production of drugs. For instance, 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propanenitrile is a key intermediate for the production of Fexofenadine, the compound of the formula II.

Fexofenadine II is an antihistamine pharmaceutical drug for the treatment of allergy symptoms and it is a bronchodilator (U.S. Pat. No. 4,254,129, Richardson-Merrell Inc.).
2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propanenitrile of the formula I is an intermediate in the synthesis of Fexofenadine and several prior art methods are described for its preparation. These methods involve procedures with a high number of intermediates as illustrated in scheme 1 below which summarizes such strategies. In U.S. Pat. No. 6,340,761, (Merrell Pharm. Inc.) the corresponding intermediates are prepared in examples 2, 3, 5 and 9 as follows. Starting from toluene III, the ketone of formula IV was obtained from Friedel-Crafts acylation with 4-chlorobutyryl chloride (Ex. 2), followed by cyclisation to yield the cyclopropyl compound V (Ex.3). The latter was brominated (compound VI) and the bromide was replaced by cyanide to yield 4-cyclopropanecarbonyl-phenyl)-acetonitrile VII (Ex. 5 and 7). Subsequent alkylation with methyl iodide furnished the desired intermediate of formula I (Ex. 9). These steps (from compounds of formula V to VII) are also described in the literature (J. Med. Chem 1973, 16, 487-490) wherein the compound of formula V was prepared starting from cyclopropylcarbonylchloride. The compound of formula I is thus obtained in a five step synthesis, involving several hazardous steps such as radical bromination, handling of highly toxic and industrially undesirable compounds such as cyanide and methyl iodide.

The preparation of the compound of formula I is further described by Wang et al. (Org. Proc. Res. and Dev. 2010, 14, 1464-68) according to scheme 2 below, wherein a compound of formula IX is converted into the compound of formula I in 4 synthetic steps consisting of alkylation of the compound of formula X via Claisen condensation to give the compound of formula XI, followed by thermal treatment to give a compound of formula XII (X═OH), functionalization to give a compound of formula XII (X═Br, Cl) and cyclisation. Even though compound of formula I is an unwanted by-product the specific conditions furnished the product up to 83% yield (Table 2, line 1). The starting material of formula IX can either be bought or and can be prepared from methyl p-toluate (VIII) in 2 steps (U.S. Pat. No. 4,598,077) in analogy to the conversion of formula V to VII described in Scheme 1 above, resulting again in a costly multistep synthesis.

An alternative synthesis of intermediate XII (X═Cl) is also described in Example 6 of U.S. Pat. No. 6,340,761, starting from the intermediate of formula XIII, prepared from cumene (XIV) in 2 steps (examples 1 and 4). This is summarized in Scheme 3 below.

While a general a 4 step process towards compound of formula I as described in Scheme 3 is possible, the conditions for conversion of a tertiary bromide of formula XIII into the tertiary nitrile of formula I are very demanding and lack industrial applicability due to an expensive, volatile and highly toxic cyanide source and need of stoichiometric quantities of a toxic tin compound.
Another approach towards the compound of formula XII is described by Di Giacomo et al. in Farmaco 1999, 54, 600-610. Starting from (4-bromo-phenyl)-2,2-dimethyl-acetonitrile (formula XV) the compound of formula XII was obtained utilizing several palladium-catalysed steps involving stannylation with the trishexabutyl tin-dimer and acylation with 4-chlorobutyryl chloride (scheme 4). Again compound XV is not a readily available commodity and needs to be prepared from precursors like p-bromo-toluene XVI, by analogous hazardous operations as mentioned in schemes 1 and 2.

Finally, another approach towards 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propanenitrile of the formula I is shown in a general scheme of U.S. Pat. No. 6,340,761 (scheme E, columns 37/38, steps h and o) and outlined in scheme 5.

Starting from benzyl nitrile XVII, dialkylation should furnish the intermediate of formula XVIII. Subsequent Friedel-Crafts-acylation with 4-chlorobutyryl chloride and cyclisation should furnish key intermediate I in a very short 3-step sequence. Unfortunately, the reactions are not described as experimental examples. An experimental verification of the reaction showed that the reaction of dimethyl-phenyl-acetonitrile of formula XVIII with 4-chlorobuturyl chloride using several variations of the Friedel Crafts acylation performed poorly. At best, the product obtained after cyclisation contained the compound of formula I in about 40% whereas the major product (about 60%) is the undesired meta-isomer of formula XIX as shown in Scheme 6 and described in reference example 1.

In summary, all of the different approaches towards the desired target 2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of the formula I as described in Schemes 1-6 above, make use of either long chemical sequences (4-5 steps) which use hazardous, highly toxic and expensive reagents (Schemes 1-4) or suffer from low yielding and unselective chemical transformations (Scheme 5-6).